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Preparation method of 5-amino-2-azaspiro [3.4] octane-2-carboxylic acid tert-butyl ester

A technology of tert-butyl carboxylate and azaspiro, which is applied in the field of compound synthesis, can solve the problem that the synthesis method is not reported in literature and the like, and achieves the effects of reasonable reaction process design, convenient operation and easy reaction.

Inactive Publication Date: 2021-03-30
南通药明康德医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There is no literature report on the synthesis method

Method used

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  • Preparation method of 5-amino-2-azaspiro [3.4] octane-2-carboxylic acid tert-butyl ester
  • Preparation method of 5-amino-2-azaspiro [3.4] octane-2-carboxylic acid tert-butyl ester
  • Preparation method of 5-amino-2-azaspiro [3.4] octane-2-carboxylic acid tert-butyl ester

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] The reaction formula of embodiment 1 is as follows:

[0036]

[0037] This embodiment adopts the following steps:

[0038] Step 1: Prepare a 10-liter three-necked bottle, mechanical stirring, thermometer, and dropping funnel. Compound 1 (191g, 1.05mol, 1.00eq) and compound 2 (187g, 1.19mol, 1.13eq) were dissolved in 2-methyltetrahydrofuran (2000mL), cooled to -60°C with dry ice, and then slowly added dropwise Lithium methylsilylamide (1.0M, tetrahydrofuran solution, 1100mL, 1.05eq), the temperature does not exceed -60°C, drop it in about 2 hours, and stir at -60°C for 2 hours after the dropwise addition. TLC showed the starting material was completely reacted. The reaction solution was quenched with 10% aqueous ammonium chloride solution (900 mL), diluted with water (800 mL), then extracted twice with methyl tert-butyl ether (600 mL), and the combined organic phases were washed with 20% aqueous citric acid solution (1500 mL) and Saturated brine (800 mL) was washed...

Embodiment 2

[0045] The reaction formula of embodiment 2 is as follows:

[0046]

[0047] This embodiment adopts the following steps:

[0048] Step 1: Prepare a 10-liter three-necked bottle, mechanical stirring, thermometer, and dropping funnel. Compound 1 (191g, 1.05mol, 1.00eq) and compound 2 (187g, 1.19mol, 1.13eq) were dissolved in 2-methyltetrahydrofuran (2000mL), cooled to -60°C with dry ice, and then slowly added dropwise Lithium methylsilylamide (1.0M, tetrahydrofuran solution, 1100mL, 1.05eq), the temperature does not exceed -60°C, drop it in about 2 hours, and stir at -60°C for 2 hours after the dropwise addition. TLC showed the starting material was completely reacted. The reaction solution was quenched with 10% aqueous ammonium chloride solution (900 mL), diluted with water (800 mL), then extracted twice with methyl tert-butyl ether (600 mL), and the combined organic phases were washed with 20% aqueous citric acid solution (1500 mL) and Saturated brine (800 mL) was washed...

Embodiment 3

[0055] The reaction formula of embodiment 3 is as follows:

[0056]

[0057] This embodiment adopts the following steps:

[0058] Step 1: Prepare a 10-liter three-necked bottle, mechanical stirring, thermometer, and dropping funnel. Compound 1 (191g, 1.05mol, 1.00eq) and compound 2 (187g, 1.19mol, 1.13eq) were dissolved in 2-methyltetrahydrofuran (2000mL), cooled to -60°C with dry ice, and then slowly added dropwise Lithium methylsilylamide (1.0M, tetrahydrofuran solution, 1100mL, 1.05eq), the temperature does not exceed -60°C, drop it in about 2 hours, and stir at -60°C for 2 hours after the dropwise addition. TLC showed the starting material was completely reacted. The reaction solution was quenched with 10% aqueous ammonium chloride solution (900 mL), diluted with water (800 mL), then extracted twice with methyl tert-butyl ether (600 mL), and the combined organic phases were washed with 20% aqueous citric acid solution (1500 mL) and Saturated brine (800 mL) was washed...

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Abstract

The invention discloses a preparation method of a compound 5-amino-2-azaspiro [3.4] octane-2-carboxylic acid tert-butyl ester. The preparation method comprises the following steps: 1. dissolving a compound 1 and a compound 2 in 2-methyl tetrahydrofuran, dropwisely adding lithium bis (trimethylsilyl) amide, and reacting to obtain a compound 3; 2, dissolving the compound 3 into acetone, and reactingwith sodium iodide to obtain a compound 4; 3, dissolving the compound 4 in 2-methyl tetrahydrofuran, dropwise adding n-butyllithium, and reacting to obtain a compound 5; 4, adding the compound 5 andamine into 1, 2-dichloroethane, then adding acetic acid and a reducing agent, and reacting to obtain a compound 6; and 5, dissolving the compound 6 in ethanol, adding a catalyst, and reacting in hydrogen to obtain a compound 7. The novel spiro compound structure is designed autonomously, a synthetic route is developed, and a synthetic method suitable for industrial production is found through continuous optimization.

Description

technical field [0001] The invention relates to a compound synthesis method, in particular to a preparation method of the compound 5-amino-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester. Background technique [0002] Compared with foreign competitors, Chinese pharmaceutical companies are often plagued by technical and financial problems, unable to effectively carry out new drug research and development, and can only simply repeat the production or imitate foreign patent expired drugs. The products lack international competitiveness, and the domestic market also suffers. The serious threat of imported western medicines, and the discovery of lead compounds is the only way to discover innovative drugs. Due to the long cycle of new drug development (8-10 years) and high cost (800-100 million US dollars), most developed countries currently adopt the method of "many, fast, high, and low cost"—combinatorial chemical technology platform to speed up the development of small...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/12
CPCC07D205/12
Inventor 金硕吴潮波杨念勇高宇徐艳
Owner 南通药明康德医药科技有限公司
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